1. Field of the Invention
The invention relates to a method for the synthesis of gem-difluorinated C-glycoside compounds derived from podophyllotoxin. It more particularly, but not exclusively, applies to the preparation of compounds which may be notably used in oncology for treating cancer.

2. Description of the Prior Art
Podophyllotoxin 1 is a lignan isolated from the roots of two plants Podophyllum peltatum (North America) and Podophyllum emodi (Asia). It has strong antimitotic activity by inhibiting polymerization of tubulin. Too toxic to be used in chemotherapy, it has given rise to many antitumoral compounds after structural modifications. Among them, glycosylated derivatives, compounds which are usually less toxic and more water-soluble, have emerged.

This the case of etoposide 2 (or VP-16) notably used in the treatment of small cell lung cancer, cancer of the bladder, of the testicles, of lymphomas, acute leukemias, Kaposi sarcomas.

Nitrogen-containing derivatives of podophyllotoxin such as GL-331 5, NPF 6 or TOP-53 7 also show very interesting activities.
All these molecules derived from the demethylepipodophyllotoxin structure are inhibitors of topoisomerase II, an enzyme which catalyses nicking and then reformation of the 2 DNA strands.
We have developed the synthesis of nitrogen-containing compounds of podophyllotoxin, with an amide function substituted with a gem-difluorinated glycoside.
The importance of the CF2 group is in addition to its resistance against biochemical degradation processes, the fact that it forms an excellent mimic of oxygen. It thereby allows synthesis of non-hydrolyzable structures.
Such compounds would be able to be used as chemotherapy agents in the treatment of different types of cancer, either alone or associated with other chemotherapies within the scope of a multitherapy.
The developed molecules belong to the series of nitrogen-containing analogs of podophyllotoxin, a family having significant cytotoxicity.
Further the presence of a glycoside is known for improving solubility in aqueous solvents, and for reducing toxicity.
The use of difluorinated analogs in the anomeric position of the glycoside further reinforces their stability against acido-basic and especially enzymatic hydrolyses.